This proposal describes a program directed at the total synthesis and investigation of the chemical biology of the five natural products everninomicin 13,384-1 (I), sangliferhin A (II), BMS-182,123 (III), CP-263,114 (IVa) and CP-225,117 (IVb). Everninomicin 13,384-1 (I) is an oligosaccharide antibiotic effective against drug-resistant pathogens and its chemical synthesis will involve construction of the requisite building blocks, followed by assembly through stereocontrolled formation of the glycosidic and orthoester bonds. Sangliferhin A (II) is a newly discovered immunosuppressant with potential in organ transplantation and cancer chemotherapy and will be constructed by assembling the required fragments on solid support and applying a Stille coupling to cyclorelease the macrocyclic system. BMS-182,123 (III) is an inhibitor of TNF-alpha production and has potential for the treatment of septic shock, inflammation and rhumatoid arthritis. Its total synthesis will be attempted via a Diels-Alder or bis-Mukaiyama reaction followed by an 87pi electrocylization process to construct its cage-like structure. The CP-molecules (IVa and IVb) are inhibitors of squalene synthase and farnesyl transferase and are relevant to cardiovascular disease (cholesterol lowering) and cancer chemotherapy. Two strategies are proposed for their total synthesis, one following an intramolecular Diels-Alder approach and the other involving a rhodium-catalyzed carbenoid generation and addition to a double bond followed by a divinylcyclopropane [3.3] sigmatropic rearrangement and a radical based ring closure to form the bicyclic skeleton.